Cancer chemotherapy generally aims to slow the growth of, or destroy, cancer cells while avoiding collateral damage to surrounding cells and tissues; the most effective anticancer agents are thus those that are best able to selectively target cancer cells while leaving normal cells relatively unaffected.
Ether lipids can be effective as anticancer agents (see, for example, Dietzfelbinger et al. (1993); Zeisig et al. (1993); Powis et al. (1990); Berdel (1991); Bhatia and Hadju (1991); Reed et al. (1991); Workman (1991); Workman et al. (1991); Bazill and Dexter (1990); Berdel (1990); Counsell et al. (1990); Tritton and Hickman (1990); Muschiol et al. (1990); Layton et al. (1980); Runge et al. (1980); Munder & Westphal (1990); Lohmeyer & Workman (1995); Lohmeyer & Biftman (1994); Great Britain Patent No. 1,583,661; U.S. Pat. No. 3,752,886). Several mechanisms of action have been proposed for the toxicity of etherlipids towards cancer cells, including the cells' lack of alkyl cleavage enzymes; the resultant inability to hydrolyze the etherlipids leads to their intracellular accumulation and to consequent damage to cell membrane lipid organization. Other potential mechanisms of etherlipid action include effects on levels of intracellular protein phosphorylation, and disruption of cellular lipid metabolism.
Normal cells typically possess the means to avoid or overcome the potentially toxic effects of etherlipids, while cancer cells do not. However, normal cells, e.g., red blood cells ("RBCs"), which do not possess such means are subject to the same disruptive effects of etherlipid action as are cancer cells. In fact, hemolysis resulting from exposure of RBCs to etherlipids has been found to be a significant impediment to the therapeutic use of the etherlipids (see, for example, Houlihan et al., 1995). One approach to solve this problem of etherlipid-induced cytotoxicity is to incorporate the drugs into lipid-based carriers, e.g., liposomes.
This invention provides a lipid-based carrier having a lamellar lipid component that contains the etherlipid and a lipid of complementary molecular shape to the etherlipid; this shape complementarity allows etherlipids to be incorporated into the lipid-based carriers at higher concentrations than would otherwise be possible. The novel combination of the etherlipids and complementarily shaped lipids in the pharmaceutical compositions of this invention has not previously been described. PCT/US95/12721 describes liposomes containing cholesterol, a phosphatidylcholine and a phosphatidylethanolamine-dicarboxylic acid derivative, in addition to a glycerol-based ether lipid having a methoxy group attached to the second position of the glycerol backbone. German Patent Application No. 4,132,345 describes liposomes containing cholesterol and a positively or negatively charged lipid in addition to a methoxy group-containing ether lipid. Japanese Patent Application No. 61-022,020 describes liposomes containing cholesterol and a phospholipid in addition to an acetyl, or propionyl, group-containing glycerol-based ether lipid. Mende et al. describes the membrane potential altering effects of liposomes containing an ether lipid/cholesterol combination of an equimolar ratio. However, none of these documents describes pharmaceutical compositions containing complementarily shaped lipids and glycerol-based ether lipids having a methoxy group at the second position.